tbuckley/cabot-search huggingface dataset:
Hypophysitis and Secondary Adrenal Insufficiency From Immune Checkpoint Inhibitors: Diagnostic Challenges and Link With Survival
Authors: Jake Johnson, Whitney Goldner, Duaa Abdallah, Fang Qiu, Apar Kishor Ganti, Anupam Kotwal
Journal: Journal of the National Comprehensive Cancer Network (2023)

Background: Hypophysitis is a serious adverse event stemming from immune checkpoint inhibitor (ICI) therapy for malignancy. This study aimed to characterize ICI-induced hypophysitis, identify diagnostic challenges, and evaluate an association with survival in a large cancer cohort. Methods: We performed a retrospective cohort study of adult patients with cancer who received ICIs between December 1, 2012, and December 31, 2019. We identified 839 patients who received CTLA-4, PD-1, or PD-L1 inhibitors or a combination thereof who were followed for a median of 19.4 months. Hypophysitis was defined as MRI evidence of pituitary gland and/or stalk enlargement or biochemical evidence of hypopituitarism if not explained by another etiology. Results: A total of 16 (1.9%) patients developed hypophysitis a median of 7 months after ICI initiation, with most patients having melanoma (9/16; 56.2%) or renal cell carcinoma (4/16; 25%). Two patients also had exogenous glucocorticoid exposure but exhibited secondary hypothyroidism and secondary adrenal insufficiency (AI). Median age at the start of ICI was 61.3 years and 57% were men. Patients who developed hypophysitis were younger compared with those who did not develop hypophysitis (median age, 57 vs 65 years; P =.011). Hypophysitis occurred most frequently after combination therapy (13.7%) compared with CTLA-4 monotherapy (1.9%), PD-1 monotherapy (1.2%), and PD-L1 monotherapy (0.8%) ( P &lt;.0001). Pituitary gland enlargement on MRI occurred more frequently after CTLA-4 inhibitor monotherapy or combination therapy (5/7; 71.4%) compared with PD-1/PD-L1 inhibitor monotherapy (1/6; 16.7%). The survival benefit of hypophysitis was not apparent after addressing immortal time bias and adjusting for other variables affecting patient outcomes. Conclusions: Secondary AI occurred in all patients, and secondary hypothyroidism occurred in half. Classic pituitary gland enlargement is usually absent in PD-1/PD-L1 inhibitor–induced hypophysitis. Further pituitary evaluation must be conducted to differentiate secondary AI resulting from exogenous glucocorticoids and hypophysitis in patients with cancer receiving ICIs. The link between hypophysitis and ICI efficacy needs further investigation.
Definition of age-dependent reference values for the diameter of the common bile duct and pancreatic duct on MRCP: a population-based, cross-sectional cohort study
Authors: Georg Beyer, Florian Kasprowicz, Anke Hannemann, Ali Aghdassi, Patrick Thamm, Henry Volzke, Markus M Lerch, Jens-Peter Kühn, Julia Mayerle
Journal: Gut (2023)

Objective Changes of the pancreaticobiliary ducts herald disease. Magnetic resonance cholangiopancreatography (MRCP) allows accurate duct visualisation. Data on reliable upper reference ranges are missing. Design Cross-sectional whole body MRI data from the population-based Study of Health in Pomerania were analysed. The width of the common bile duct (CBD) and the pancreatic duct (PD) was determined. We aimed to describe the distribution of physiological duct diameters on MRCP in a population of healthy subjects and to identify factors influencing duct size. Results After excluding pre-existing pancreaticobiliary conditions, CBD and PD diameters from 938 and 774 healthy individuals, respectively, showed a significant increase with age (p&lt;0.0001) and exceeded the conventional upper reference limit of normal in 10.9% and 18.2%, respectively. Age-dependent upper reference limits of duct diameters were delineated with non-parametric quantile regression, defined as 95th percentile: for CBD up to 8 mm in subjects &lt;65 years and up to 11 mm in subjects ≥65 years. For the PD reference diameters were up to 3 mm in subjects &lt;65 years and up to 4 mm in subjects ≥65 years. Conclusions This is the first population-based study delineating age-adjusted upper reference limits of CBD and PD on MRCP. We showed that up to 18.2% of healthy volunteers would have needed diagnostic workup, if the conventional reference values were used. The utilisation of the adapted reference levels may help to avoid unnecessary investigations and thus to reduce healthcare expenditure and test-related adverse events.
Age-associated B cells are heterogeneous and dynamic drivers of autoimmunity in mice
Authors: Kevin M. Nickerson, Shuchi Smita, Kenneth B. Hoehn, Anthony D. Marinov, Kayla B. Thomas, Justin T. Kos, Yi Yang, Sheldon I. Bastacky, Corey T. Watson, Steven H. Kleinstein, Mark J. Shlomchik
Journal: The Journal of Experimental Medicine (2023)

Age-associated B cells (ABCs) are formed under inflammatory conditions and are considered a type of memory B cell (MBC) expressing the transcription factor T-bet. In SLE, ABC frequency is correlated with disease, and they are thought to be the source of autoantibody-secreting cells. However, in inflammatory conditions, whether autoreactive B cells can become resting MBCs is uncertain. Further, the phenotypic identity of ABCs and their relationship to other B cell subsets, such as plasmablasts, is unclear. Whether ABCs directly promote disease is untested. Here we report, in the MRL/lpr SLE model, unexpected heterogeneity among ABC-like cells for expression of the integrins CD11b and CD11c, T-bet, and memory or plasmablast markers. Transfer and labeling studies demonstrated that ABCs are dynamic, rapidly turning over. scRNA-seq identified B cell clones present in multiple subsets, revealing that ABCs can be plasmablast precursors or undergo cycles of reactivation. Deletion of CD11c-expressing B cells revealed a direct role for ABC-like B cells in lupus pathogenesis.
Hidden behavioral fingerprints in epilepsy
Authors: Tilo Gschwind, Ayman Zeine, Ivan Raikov, Jeffrey E. Markowitz, Winthrop F. Gillis, Sylwia Felong, Lori L. Isom, Sandeep Robert Datta, Ivan Soltesz
Journal: Neuron (2023)

Epilepsy is a major disorder affecting millions of people. Although modern electrophysiological and imaging approaches provide high-resolution access to the multi-scale brain circuit malfunctions in epilepsy, our understanding of how behavior changes with epilepsy has remained rudimentary. As a result, screening for new therapies for children and adults with devastating epilepsies still relies on the inherently subjective, semi-quantitative assessment of a handful of pre-selected behavioral signs of epilepsy in animal models. Here, we use machine learning-assisted 3D video analysis to reveal hidden behavioral phenotypes in mice with acquired and genetic epilepsies and track their alterations during post-insult epileptogenesis and in response to anti-epileptic drugs. These results show the persistent reconfiguration of behavioral fingerprints in epilepsy and indicate that they can be employed for rapid, automated anti-epileptic drug testing at scale.
Correction: Anti-malaria drug artesunate prevents development of amyloid-β pathology in mice by upregulating PICALM at the blood-brain barrier
Authors: Kassandra Kisler, Abhay P. Sagare, Divna Lazic, Sam Bazzi, Erica Lawson, Ching-Ju Hsu, Yaoming Wang, Anita Ramanathan, Amy R. Nelson, Zhen Zhao, Berislav V. Zlokovic
Journal: Molecular Neurodegeneration (2023)
Orthostatic tachycardia after covid-19
Authors: Ana B Espinosa-Gonzalez, Harsha Master, Nicholas Gall, Stephen Halpin, Natalie Rogers, Trisha Greenhalgh
Journal: BMJ (2023)

### What you need to know Patients with long covid—defined by the National Institute for Health and Care Excellence (NICE) as signs and symptoms that persist for more than four weeks (and especially more than 12 weeks) following acute covid-1912—may present in primary care with symptoms of palpitations (tachycardia) triggered by standing or minimal exertion.3 These may be accompanied by dizziness, breathlessness, chest pain, sweating, bloating, fatigue, and other symptoms which may be caused by a dysfunction of the autonomic nervous system (dysautonomia).45678910111213 Patients can find these symptoms debilitating and they can affect function and mood. Limited evidence, variable diagnostic criteria, uncertainty around cause and pathogenesis, and the absence of licensed medications, have all contributed to making this a difficult condition to diagnose and manage. In this practice pointer, we offer an overview of orthostatic tachycardia following covid-19, including a summary of the key steps for diagnosis and management. Prevalence estimates vary depending on sample and setting, but indicate that about 25% of long covid patients may have dysautonomia14 and 2-14% will develop orthostatic tachycardia (postural orthostatic tachycardia syndrome) six to eight months after infection.341516Box 1 provides more information on these conditions. The assessment and management is summarised in the infographic. Box 1 ### Dysautonomia and postural orthostatic tachycardia syndromes The autonomic nervous system is responsible for the unconscious regulation of many physiological processes, including heart rate, blood pressure, respiration, and digestion. The broad category of "dysautonomia" encompasses several conditions, from the intermittent "faint" (neurocardiogenic syncope) through more pervasive dysregulation (postural … RETURN TO TEXT
A diverse public health workforce is more important than ever
Authors: Kazim Beebeejaun, Kerry Littleford
Journal: BMJ (2023)

19 pandemic can prepare us for the future of public health, write Kazim Beebeejaun and Kerry Littleford Kazim Beebeejaun, Kerry LittlefordThe covid-19 pandemic provided an opportunity to learn and rethink what a well equipped public health workforce looks like.To tackle health inequalities meaningfully and build long term trust with deprived communities in the UK, we must first confront inequities and biases in our own profession.
Survival in hematological malignancies in the Nordic countries through a half century with correlation to treatment
Authors: Kari Hemminki, Janne Hemminki, Asta Försti, Amit Sud
Journal: Leukemia (2023)

Abstract Studies of survival in hematological malignancies (HMs) have generally shown an improvement over time, although most of these studies are limited by a short follow-up period. Using the NORDCAN database with data from Denmark, Finland, Norway and Sweden, we follow periodic increases in relative survival in seven HMs through half a century up to 2015–2019. Five-year survival improved in all seven HMs, reaching 90% for Hodgkin lymphoma (HL), myeloproliferative neoplasias and chronic lymphocytic leukemia (CLL), 60% for multiple myeloma (MM) and chronic myeloid leukemias (CMLs), 50% for the myelodysplastic syndromes and 30% for acute myeloid leukemia (AML). Improvements in survival over 50 years ranged from 20% to more than 50% units across the different HMs. The likely reasons for such progress include earlier diagnoses, improved risk stratification and advances in treatment. We observed differing temporal trends in improvements in survival. The gradual increases observed in HL, CLL and AML highlight the impact of optimization of existing therapies and improvements in diagnostics and risk stratification, whereas the rapid increases observed in the CMLs and MM highlight the impact of novel therapies. Recent therapeutic advances may further improve survival in HMs where survival remains low such as in AML.
Impact of Elotuzumab Plus Pomalidomide/Dexamethasone on Health-related Quality of Life for Patients With Relapsed/Refractory Multiple Myeloma: Final Data From the Phase 2 ELOQUENT-3 Trial
Authors: Katja Weisel, Meletios A. Dimopoulos, Jesús San-Miguel, Agne Paner, Monika Engelhardt, Fiona Taylor, Jennifer Lord-Bessen, Christine Yip, Mike Greenwood, Jackson Tang, Michele Cavo
Journal: HemaSphere (2023)

Triplet regimens containing immunomodulatory drugs and proteasome inhibitors (PIs) have improved outcomes and extended survival for patients with relapsed/refractory multiple myeloma (RRMM). We evaluated updated health-related quality of life (HRQoL) findings from the phase 2 ELOQUENT-3 clinical trial (NCT02654132) after 4 years of treatment with elotuzumab plus pomalidomide and dexamethasone (EPd) and assessed the impact of the addition of elotuzumab on patients' HRQoL. HRQoL was assessed as an exploratory endpoint using the MD Anderson Symptom Inventory for Multiple Myeloma (MDASI-MM), which evaluates symptom severity, symptom interference, and HRQoL, and the 3-level EQ-5D, a patient-reported measure of health utility and general health. Statistical analyses included descriptive responder, longitudinal mixed-model, and time-to-first-deterioration (TTD) analyses using prespecified minimally important differences and responder definitions. Of 117 randomized patients, 106 (EPd, n = 55; pomalidomide and dexamethasone [Pd], n = 51) were eligible for inclusion in HRQoL analyses. Completion rates at almost all on-treatment visits were ≥80%. The proportion of patients treated with EPd who improved or maintained stable HRQoL until cycle 13 ranged from 82% to 96% for MDASI-MM total symptom score and 64% to 85% for MDASI-MM symptom interference. Across measurements, there were no clinically meaningful differences in changes from baseline between treatment arms, and TTD was not significantly different for EPd versus Pd. In conclusion, HRQoL was not impacted by the addition of elotuzumab to Pd and did not significantly deteriorate in patients with RRMM previously treated with lenalidomide and a PI in ELOQUENT-3.
Bioengineered materials with selective antimicrobial toxicity in biomedicine
Authors: Pooyan Makvandi, Hao Song, Cynthia K. Y. Yiu, Rossella Sartorius, Ehsan Nazarzadeh Zare, Navid Rabiee, Wei-Xi Wu, Ana Cláudia Paiva-Santos, Xiang-Dong Wang, Cheng-Zhong Yu, Franklin R. Tay
Journal: Military Medical Research (2023)

Abstract Fungi and bacteria afflict humans with innumerous pathogen-related infections and ailments. Most of the commonly employed microbicidal agents target commensal and pathogenic microorganisms without discrimination. To distinguish and fight the pathogenic species out of the microflora, novel antimicrobials have been developed that selectively target specific bacteria and fungi. The cell wall features and antimicrobial mechanisms that these microorganisms involved in are highlighted in the present review. This is followed by reviewing the design of antimicrobials that selectively combat a specific community of microbes including Gram-positive and Gram-negative bacterial strains as well as fungi. Finally, recent advances in the antimicrobial immunomodulation strategy that enables treating microorganism infections with high specificity are reviewed. These basic tenets will enable the avid reader to design novel approaches and compounds for antibacterial and antifungal applications.
Using protein-per-mRNA differences among human tissues in codon optimization
Authors: Xavier Hernandez-Alias, Hannah Benisty, Leandro G. Radusky, Luis Serrano, Martin H. Schaefer
Journal: Genome biology (2023)

Abstract Background Codon usage and nucleotide composition of coding sequences have profound effects on protein expression. However, while it is recognized that different tissues have distinct tRNA profiles and codon usages in their transcriptomes, the effect of tissue-specific codon optimality on protein synthesis remains elusive. Results We leverage existing state-of-the-art transcriptomics and proteomics datasets from the GTEx project and the Human Protein Atlas to compute the protein-to-mRNA ratios of 36 human tissues. Using this as a proxy of translational efficiency, we build a machine learning model that identifies codons enriched or depleted in specific tissues. We detect two clusters of tissues with an opposite pattern of codon preferences. We then use these identified patterns for the development of CUSTOM, a codon optimizer algorithm which suggests a synonymous codon design in order to optimize protein production in a tissue-specific manner. In human cell-line models, we provide evidence that codon optimization should take into account particularities of the translational machinery of the tissues in which the target proteins are expressed and that our approach can design genes with tissue-optimized expression profiles. Conclusions We provide proof-of-concept evidence that codon preferences exist in tissue-specific protein synthesis and demonstrate its application to synthetic gene design. We show that CUSTOM can be of benefit in biological and biotechnological applications, such as in the design of tissue-targeted therapies and vaccines.
The genetic and evolutionary basis of gene expression variation in East Africans
Authors: Derek E. Kelly, Shweta Ramdas, Rong Ma, Renata A. Rawlings-Goss, Gregory R. Grant, Alessia Ranciaro, Jibril B. Hirbo, William Beggs, Meredith Yeager, Stephen Chanock, Thomas B. Nyambo, Sabah A. Omar, Dawit Woldemeskel, Gurja Belay, Hongzhe Li, Christopher D. Brown, Sarah A. Tishkoff
Journal: Genome biology (2023)

Mapping of quantitative trait loci (QTL) associated with molecular phenotypes is a powerful approach for identifying the genes and molecular mechanisms underlying human traits and diseases, though most studies have focused on individuals of European descent. While important progress has been made to study a greater diversity of human populations, many groups remain unstudied, particularly among indigenous populations within Africa. To better understand the genetics of gene regulation in East Africans, we perform expression and splicing QTL mapping in whole blood from a cohort of 162 diverse Africans from Ethiopia and Tanzania. We assess replication of these QTLs in cohorts of predominantly European ancestry and identify candidate genes under selection in human populations.
DIMPLE: deep insertion, deletion, and missense mutation libraries for exploring protein variation in evolution, disease, and biology
Authors: Christian B. Macdonald, David Nedrud, Patrick Rockefeller Grimes, Donovan Trinidad, James S. Fraser, Willow Coyote-Maestas
Journal: Genome biology (2023)

Abstract Insertions and deletions (indels) enable evolution and cause disease. Due to technical challenges, indels are left out of most mutational scans, limiting our understanding of them in disease, biology, and evolution. We develop a low cost and bias method, DIMPLE, for systematically generating deletions, insertions, and missense mutations in genes, which we test on a range of targets, including Kir2.1. We use DIMPLE to study how indels impact potassium channel structure, disease, and evolution. We find deletions are most disruptive overall, beta sheets are most sensitive to indels, and flexible loops are sensitive to deletions yet tolerate insertions.
Clinicohematologic and molecular response of essential thrombocythemia patients treated with pegylated interferon-α: a multi-center study of the German Study Group-Myeloproliferative Neoplasms (GSG-MPN)
Authors: Frank Stegelmann, Lino L. Teichmann, Florian H. Heidel, Carl C. Crodel, Thomas Ernst, Sebastian Kreil, Andreas Reiter, Sara Otten, Stefanie Schauer, Ruth-Miriam Körber, Kim Kricheldorf, Susanne Isfort, Hartmut Döhner, Tim H. Brümmendorf, Martin Griesshammer, Konstanze Döhner, Steffen Koschmieder
Journal: Leukemia (2023)
Dynamic monitoring of myeloma minimal residual disease with targeted mass spectrometry
Authors: Somayya Noori, Charissa Wijnands, Pieter Langerhorst, Vincent Bonifay, Christoph Stingl, Cyrille Touzeau, Jill Corre, Aurore Perrot, Philippe Moreau, Hélène Caillon, Theo M. Luider, Thomas Dejoie, Joannes F. M. Jacobs, Martijn M. van Duijn
Journal: Blood Cancer Journal (2023)
Limited commercialization of artificial intelligence technology in the diagnosis of pigmented lesions despite explosive growth in published programs
Authors: Sarah B. Kooper-Johnson, Maya Weber, Shaundra Eichtadt, Bichchau Michelle Nguyen
Journal: Journal of the American Academy of Dermatology (2023)

To the Editor: Publications of artificial intelligence programs designed for diagnosing pigmented lesions and melanoma have skyrocketed as reports suggest they produce similar results to clinical assessments.1,2 Several smartphone applications have also been developed to classify these lesions. However, their consistency has been called into question.3 With all the buzz, the question remains as to why commercial applications have been so limited.
Dermatopathologic features of cutaneous squamous cell carcinoma and actinic keratosis: Consensus criteria and proposed reporting guidelines
Authors: Rachel E. Christensen, Dirk M. Elston, Brandon Worley, McKenzie A. Dirr, Noor Anvery, Bianca Y. Kang, Soon Bahrami, Robert T. Brodell, Lorenzo Cerroni, Carly Elston, Tammie Ferringer, M. Yadira Hurley, Kyle Garton, Joyce Siong See Lee, Yeqiang Liu, John C. Maize, Jennifer M. McNiff, Ronald P. Rapini, Omar P. Sangueza, Christopher R. Shea, Cheng Zhou, Murad Alam
Journal: Journal of the American Academy of Dermatology (2023)
Sporothrix brasiliensis genotyping reveals numerous independent zoonotic introductions in Brazil
Authors: Bram Spruijtenburg, Amanda Bombassaro, Eelco F.J. Meijer, Anderson Messias Rodrigues, Maria Eduarda Grisolia, Vânia Aparecida Vicente, Flavio de Queiroz-Telles, Jacques F. Meis, Theun de Groot
Journal: Journal of Infection (2023)
UHRF1/DNMT1–MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancer
Authors: Shuye Lin, Hanli Xu, Lin Qin, Mengdi Pang, Ziyu Wang, Meng Gu, Lishu Zhang, Cong Zhao, Xuefeng Hao, Zhiyun Zhang, Weimin Ding, Jianke Ren, Jiaqiang Huang
Journal: Acta Pharmaceutica Sinica B (2023)

As confusion mounts over RNA isoforms involved in phenotypic plasticity, aberrant CpG methylation-mediated disruption of alternative splicing is increasingly recognized as a driver of intratumor heterogeneity (ITH). Protease serine 3 (PRSS3), possessing four splice variants (PRSS3-SVs; PRSS3-V1-V4), is an indispensable trypsin that shows paradoxical effects on cancer development. Here, we found that PRSS3 transcripts and their isoforms were divergently expressed in lung cancer, exhibiting opposing functions and clinical outcomes, namely, oncogenic PRSS3-V1 and PRSS3-V2 versus tumor-suppressive PRSS3-V3, by targeting different downstream genes. We identified an intragenic CpG island (iCpGI) in PRSS3. Hypermethylation of iCpGI was mediated by UHRF1/DNMT1 complex interference with the binding of myeloid zinc finger 1 (MZF1) to regulate PRSS3 transcription. The garlic-derived compound diallyl trisulfide cooperated with 5-aza-2'-deoxycytidine to exert antitumor effects in lung adenocarcinoma cells through site-specific iCpGI demethylation specifically allowing MZF1 to upregulate PRSS3-V3 expression. Epigenetic silencing of PRSS3-V3 via iCpGI methylation (iCpGIm) in BALF and tumor tissues was associated with early clinical progression in patients with lung cancer but not in those with squamous cell carcinoma or inflammatory disease. Thus, UHRF1/DNMT1-MZF1 axis-modulated site-specific iCpGIm regulates divergent expression of PRSS3-SVs, conferring nongenetic functional ITH, with implications for early detection of lung cancer and targeted therapies.